1. Field of the Invention
The present invention relates to a process for preparing an antihypercholesterolemia agent, simvastatin, and in particular to a process for preparing simvastatin.
2. Description of Related Art
Antihypercholesterolemia agents such as simvastatin (compound 6), 6(R)-{2-8'(S)-2",2"-dimethylbutyryloxy-2'(S)-6'(R)-dimethyl-1',2',6',7',8' 8'a(R)-hexahydro-napthyl-1'(S)-ethyl}-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-py ran-2-one are strong inhibitors of the biosynthesis of cholesterol. Simvastatin is prepared from the raw material lovastatin (compound 1). The 8'-ester group on the polyhydronaphthyl ring of the raw material, lovastatin 1, is hydrolyzed to form an 8'-hydroxy derivative 2. The 4-hydroxyl group on the lactone ring of 2 is then protected with t-butyldimethylchlorosilane in an inert atmosphere at ambient temperature in the presence of an acid acceptor such as imidazole to form a .beta.-protected compound 3. The 8'-hydroxy group on the polyhydronaphthyl ring of compound 3 is then acylated to provide protected ester, compound 4. After removal of the silyl protecting group, the desired product 6, sinvastatin is obtained. The reaction scheme of the above process is indicated below. ##STR1##
Since compound 3 is highly sterically hindered, acylation of 3 is cumbersome. U.S. Pat. No. 4,845,237 discloses an acylation process involving treatment of the desired acyl group with acid chloride in pyridine in the presence of 4-4-dimethylaminopyridine (DMAP) and lithium bromide as catalysts. U.S. Pat. No. 4,444,784 discloses an acylation process comprising treatment of the 8'-polyhydronaphthol with the free acid of the desired acyl group in the presence of N', N'-dicyclohexylcarbodimide with 4-pyrrolidinopyridine as a catalyst in dichloromethane.
The two acylation processes require prolonged high reaction temperatures (100.degree. C., 4 hours) and a large quantity of acyl chloride (usually more than 4 equivalents). The formation of a significant amount of side product and the acyl chloride remaining, causes a poor yield in the recovery of the acylated product. On the other hand, the hygroscopic alkali metal bromide (i.e., lithium bromide) requires special treatment and handling.